Long term control of blood pressure is mediated predominantly by maintenance of salt balance by the kidneys. This physiological control is enabled by renal tubular transport of Na and Cl. To date, most monogenic forms of abnormal blood pressure control involve genes that converge on this final common pathway, altering blood pressure by changing net renal salt reabsorption. Essential hypertension is genetically more complex but may also represent subtle defects in regulating renal salt balance. In the thick ascending limb (TAL), a basolateral chloride channel complex mediates basolateral Cl efflux and is necessary for transepithelial salt reabsorption by this nephron segment. This channel complex is composed of two proteins, a pore forming subunit (ClC-Kb encoded by CLCNKB) and an accessory subunit (barttin encoded by BSND). The physiological importance of this channel is illustrated by the finding that patients with loss-of-function mutations have Bartter syndrome characterized by marked salt-wasting and hypotension. By contrast to the known clinical phenotype associated with loss of function mutations in this Cl channel complex, the clinical implications of gain-of-function mutations in either CLCNKB or BSND are unknown. We hypothesize that genetic variation in either CLCNKB, BSND or both genes predispose to abnormal blood pressure phenotypes including essential hypertension. To explore this idea, we propose to define and functionally characterize CLCNKB and BSND polymorphisms in coding and regulatory regions. We will then test for genetic association in cohorts of patients with essential hypertension and appropriate matched normotensive controls. Case-control, gene-gene interactions and haplotype analysis will be used to probe for associations between Cl channel variants and blood pressure phenotypes. This multidisciplinary approach to characterize renal Cl channel genetic variation and test for genetic association in hypertension will expand our knowledge of the role of these molecules in blood pressure regulation and disease. This Mentored Clinical Scientist Development Award will provide protected time for combined research and didactic training in genetics, molecular biology, and ion channel physiology along with career guidance by senior faculty to a promising physician-scientist seeking success as an independent investigator in academic nephrology studying the molecular basis of hypertension and kidney disease.